Hydrogen sulphate (alpha S) of the alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel hydrogen sulphate) of formula I
is an anti-thrombotic agent that has been described in patent CZ 274 420 (EP 281 459), dealing with the technology for manufacturing dextrorotatory S enantiomer. The manufacturing method disclosed in the cited patent dwells in reacting the racemic mixture with optically active camphor sulphonic acid and subsequent separating the diastereoisomer.
The respective salt of clopidogrel with camphor sulphonic acid is transformed with sodium hydrogen carbonate solution in methylene chloride environment into the optically active base, which is obtained by evaporation of the solvent.
The evaporation residue—the optically active base of clopidogrel—is dissolved in acetone, where it is transformed into hydrogen sulphate by adding drops of an equivalent amount of sulphuric acid, under cooling with crushed ice. The melting temperature of the resulting precipitate is stated as 184° C.
The specification of CZ 274 420 (EP 281 459) does not deal with the crystalline form of clopidogrel hydrogen sulphate prepared in this way. A newer patent application, CZ 2000-4637 (WO 99/65915) gives a description of crystalline Forms I and II of clopidogrel hydrogen sulphate. According to this more recent patent application, the precipitation method described in CZ 274 420 (EP 281 459) had led to crystalline Form I. The above application defines an allegedly new crystalline form, Form II. The process for obtaining Form II according to example 1A of this application dwells in introduction of the salt of clopidogrel with camphor sulphonic acid into methylene chloride and its transformation into the base with a solution of potassium carbonate. Methylene chloride is evaporated and the evaporation residue is dissolved in acetone. By adding sulphuric acid, the hydrogen sulphate precipitates out of acetone.
The methods leading—according to the application CZ 2000-4637 (WO 99/65915)—to Form II, are thus very similar to those leading to Form I according to the same application. Since, moreover, the application defines Form II as thermodynamically more stable, it is obvious that the known methods allegedly resulting in Form I will be poorly reproducible. It can be assumed that even a small change in conditions will result in Form II instead of expected Form I. The Form I under generation can, under these circumstances, transform spontaneously into Form II and it can be expected that it will be at least contaminated with Form II.
The above stated expectations have been proven experimentally.
The present invention provides a reliable method for obtaining Form I of clopidogrel hydrogen sulphate without detectable impurity of Form II.